Simultaneous inhibition of aberrant cancer kinome using rationally designed polymer-protein core-shell nanomedicine

Simultaneous inhibition of deregulated cancer kinome using rationally designed nanomedicine is an advanced therapeutic approach. Herein, we have developed a polymer-protein core-shell nanomedicine to inhibit critically aberrant pro-survival kinases (mTOR, MAPK and STAT5) in primitive (CD34+/CD38−) Acute Myeloid Leukemia (AML) cells. The nanomedicine consists of poly-lactide-co-glycolide core (~ 250 nm) loaded with mTOR inhibitor, everolimus, and albumin shell (~ 25 nm thick) loaded with MAPK/STAT5 inhibitor, sorafenib and the whole construct was surface conjugated with monoclonal antibody against CD33 receptor overexpressed in AML. Electron microscopy confirmed formation of core-shell nanostructure (~ 290 nm) and flow cytometry and confocal studies showed enhanced cellular uptake of targeted nanomedicine. Simultaneous inhibition of critical kinases causing synergistic lethality against leukemic cells, without affecting healthy blood cells, was demonstrated using immunoblotting, cytotoxicity and apoptosis assays. This cell receptor plus multi-kinase targeted core-shell nanomedicine was found better specific and tolerable compared to current clinical regime of cytarabine and daunorubicin.From the Clinical EditorThese authors demonstrate simultaneous inhibition of critical kinases causing synergistic lethality against leukemic cells, without affecting healthy blood cells by using rationally designed polymer-protein core-shell nanomedicine, provoding an advanced method to eliminate cancer cells, with the hope of future therapeutic use.

Graphical AbstractAberrant cancer kinome is an important target for the development of new generation cancer nanomedicines. Here, we present a novel, CD33 targeted polymer-protein core-shell nanomedicine encapsulating two different protein kinase inhibitors targeting aberrant mTOR, MAPK and STAT5 signalling in primitive Acute Myeloid Leukemia (AML; CD34+CD38−CD33+) cells. This cell receptor plus multi-kinase targeted nano-therapy showed highly specific anti-leukemic activity compared to the clinically used cytotoxic drug combination of cytarabine and daunorubicin.Figure optionsDownload high-quality image (227 K)Download as PowerPoint slide